PB1850: A DOSE FINDING AND EXPANSION OPEN LABEL, MULTICENTER STUDY OF IADADEMSTAT AND GILTERITINIB IN PATIENTS WITH RELAPSE/REFRACTORY ACUTE MYELOID LEUKEMIA WITH MUTATED FLT3: THE FRIDA STUDY
Authors: A. Fathi, A. Molero, S. Gutierrez, M. Arévalo, H. Yang, C. Buesa, A. Limon
Journal: HemaSphere (2022)

Background: Despite improvements in therapy for acute myeloid leukemia (AML), relapses remain a common challenge, contributing to the death of more than 50% of AML patients (pts). Approximately a third of pts with newly diagnosed AML harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. Current guidelines recommend molecular testing for FLT3-mut at diagnosis and at relapse, for earlier incorporation of targeted agents FLT3 inhibitors (FLT3i). The approval of the FLT3i midostaurin with induction therapy in FLT3mut AML, and of a more specific potent FLT3i, gilteritinib, as monotherapy for relapsed/refractory (R/R) pts have resulted in improved outcomes. Nevertheless, the duration of remission achieved with single-agent gilteritinib in R/R disease is transient and often brief. Iadademstat (iada) is a highly selective and potent covalent inhibitor of LSD1/KDM1A (lysine demethylase 1) that induces differentiation of AML cells in vitro and decreases leukemic stem cell survival in preclinical models. More than 100 subjects have been treated with iada, including R/R AML pts with monotherapy and naïve AML pts in combination with azacitidine, revealing a manageable safety profile and encouraging response rates. The purpose of the FRIDA clinical trial is to evaluate the safety and effect of iada in combination with the standard-of-care gilteritinib for the treatment of R/R FLT3-mut AML pts. The preclinical rationale supporting the combination is based on: 1) a potent synergistic activity in FLT3-AML in several preclinical models, and 2) the anti-leukemic activity of iada, mediated by preventing the interaction between LSD1 and the GFI1 transcription factor and modifying the epigenetic marks of genes resulting on macrophage/monocytic differentiation. These data, together with iada’s favorable ADME and low DDI risk, warrants further exploration of this combination with the aim of improving outcomes for FLT3-mut R/R AML pts. Aims: The FRIDA study will establish the safety, tolerability and determine the recommended phase 2 dose (RP2D), and preliminary activity for the combination of iada and gilteritinib in pts with FLT3mut R/R AML. Methods: Adult pts with a body weight >50Kg and ECOG 0-2, with relapsed or refractory disease, after 1 or 2 prior lines of therapy, and with FLT3-mutations will be enrolled. In a 3 + 3 escalation phase, up to 18 pts would receive iada at doses of 75 to 150 ug, orally, on 5 days ON -2 days OFF schedule, with continuous gilteritinib PO, at 120 mg/day. In the expansion phase, up to 14 pts at the selected safe and pharmacologically active dose/s will be enrolled. Primary endpoints of the study are safety and RP2D determination (based on PK, PD, safety, tolerability, and preliminary activity). Bayesian efficacy monitoring will be performed with cumulating enrollment to ensure futility boundaries are not crossed and to evaluate the activity of the combination. Secondary endpoints include Overall Survival, Event-Free-Survival, Overall Response Rate, Time to Response, Duration of Response and Transfusion rate. Exploratory endpoints include measurable residual disease and gene mutational analysis. Results: This is a clinical trial in progress. No results available. Summary/Conclusion: Study recruiting in Q2 2022 in US.